Atrial defibrillation methods and apparatus

ABSTRACT

Methods and apparatus for achieving atrial defibrillation in a heart. Atrial pacing is first conducted from a single pacing site so as to have the desired effect of maximizing the extent of phase-locked area of atrial tissue. Next, an ADF shock is introduced, if still needed, to achieve atrial defibrillation. ADFT energy requirements have been shown to be dramatically reduced on account of using a pacing rate set proportionally to the atrial fibrillation cycle length such that large areas of atrial tissues are phase-locked, and consequently atrial defibrillation can be effected in the patient with greatly reduced energy requirements for ADFTs.

BACKGROUND OF THE INVENTION

The present invention generally relates to cardiac therapy, and, moreparticularly, the present invention is concerned with cardiac therapiesinvolving controlled delivery of electrical stimulations to a heart fortreatment of atrial arrhythmias and an apparatus for delivering suchtherapies.

Cardiac arrhythmias can generally be thought of as disturbances of thenormal rhythm of the heart muscle. Cardiac arrhythmias are broadlydivided into two major categories, bradyarrhythmia and tachyarrhythmia.Tachyarrhythmia can be broadly defined as an abnormally rapid heart(e.g., over 100 beats/minute, at rest), and bradyarrhythmia can bebroadly defined as an abnormally slow heart (e.g., less than 50beats/minute). Tachyarrhythmias are further subdivided into two majorsub-categories, namely, tachycardia and fibrillation. Tachycardia is acondition in which the electrical activity and rhythms of the heart arerapid, but organized. Fibrillation is a condition in which theelectrical activity and rhythm of the heart are rapid, chaotic, anddisorganized. Tachycardia and fibrillation are further classifiedaccording to their location within the heart, namely, either atrial orventricular. In general, atrial arrhythmias are non-life threatening,chronic conditions, because the atria (upper chambers of the heart) areonly responsible for aiding the movement of blood into the ventricles(lower chambers of the heart), whereas ventricular arrhythmias arelife-threatening, acute events, because the heart's ability to pumpblood to the rest of the body is impaired if the ventricles becomearrhythmic. This invention is particularly concerned with treatment ofatrial fibrillation.

Various types of implantable cardiac stimulation devices are presentlyavailable and used for delivering various types of cardiac stimulationtherapy in the treatment of cardiac arrhythmias. The two most commontypes which are in widespread use are pacemakers and implantablecardioverter defibrillators (ICDs). Pacemakers generally producerelatively low voltage pacing pulses which are delivered to thepatient's heart through low voltage, bipolar pacing leads, generallyacross spaced apart ring and tip electrodes thereof which are ofopposite polarity. These pacing pulses assist the natural pacingfunction of the heart in order to prevent bradycardia.

On the other hand, ICDs are sophisticated medical devices which aresurgically implanted (abdominally or pectorally) in a patient to monitorthe cardiac activity of the patient's heart, and to deliver electricalstimulation as required to correct cardiac arrhythmias which occur dueto disturbances in the normal pattern of electrical conduction withinthe heart muscle. In general, an ICD continuously monitors the heartactivity of the patient in whom the device is implanted by analyzingelectrical signals, known as electrograms (EGMs), detected byendocardial (intracardiac) sensing electrodes positioned in the rightventricular apex and/or right atrium of the patient's heart, orelsewhere in the heart. More particularly, contemporary ICDs includewaveform digitization circuitry which digitizes the analog EGM producedby the sensing electrodes, and a microprocessor and associatedperipheral integrated circuits (ICs) which analyze the digitized EGM inaccordance with a diagnostic algorithm implemented by software stored inthe microprocessor. Contemporary ICDs are generally capable ofdiagnosing the various types of cardiac arrhythmias discussed above, andthen delivering the appropriate electrical stimulation/therapy to thepatient's heart, in accordance with a therapy delivery algorithm alsoimplemented in software stored in the microprocessor, to thereby corrector terminate the diagnosed arrhythmias. Typical electrical stimulusdelivery means used in ICDs involve an energy storage device, e.g., acapacitor, connected to a shock delivering electrode or electrodes.Contemporary ICDs are capable of delivering various types or levels ofelectrical therapy. U.S. Pat. No. 5,545,189 provides a representativebackground discussion of these and other details of conventional ICDs,and the disclosure of this patent is herein incorporated by reference.

In the treatment of a chronic cardiac condition, such as atrialarrhythmias, a challenge posed is that the patient typically isconscious and can potentially perceive any programmed electricalstimulation treatment being performed on his/her heart. Namely, oneknown method of electrical shock therapy for treating atrial (orventricular) arrhythmia is to deliver a single burst of a relativelylarge amount of electrical current through the fibrillating heart of apatient. For a given atrial fibrillation episode, the minimum amount ofenergy required to defibrillate a patient's atrium is known as theatrial defibrillation threshold (ADFT). Generally speaking, the degreeof pain, discomfort and trauma caused to the conscious patient receivingelectrical stimulation as the mode of therapy for a cardiac fibrillationgenerally will be a direct function of the amount of electrical energydelivered to the patient's heart to terminate a given fibrillationepisode.

Therefore, it is desirable that the energy levels of electricalstimulating shocks delivered by an implantable atrial defibrillator bereduced as much as possible, and ideally to below the pain threshold ofthe patient. Although the sensitivity to a electrical stimulus can varyfrom patient to patient in cardiac therapy, a current goal in the fieldof cardiac medicine is to reduce atrial defibrillation thresholds(ADFTs) to less than 1.0 joule, and more preferably, below 0.5 joule, tothereby reduce the required energy level of the defibrillation shocks tobelow the conscious perception levels of the vast majority of patients.

The electrical current and voltage requirements for conducting cardiacpacing therapy are relatively nominal in comparison to ADFTs.Consequently, the effects of pacing on atrial fibrillation has been thesubject of several prior studies. However, previously reported studiesof using local pacing alone to terminate atrial fibrillation have notindicated success. For instance, M. Allessie, et al., Circulation, vol.84, No. 4, October 1991, pp. 1689-1697 and C. Kirchoff, et al.,Circulation, vol. 88, No. 2, Aug. 1993, pp. 736-749, describe use ofrapid pacing in conscious dogs at a single atrial site at a rate fasterthan the atrial fibrillation cycle length to achieve a limited localcapture but without termination of atrial fibrillation. These priorresearchers demonstrated that during atrial fibrillation, a short andvariable excitable gap occurs after local tissue emerges from the localrefractory period when the cardiac tissue can be easily excited by adelivered pulse to achieve local capture before the next fibrillatorywavefront comes close enough to activate the area again.

If the cardiac tissue was homogenous, the pulsing from the one siteshould eventually entrain all available atrial tissue to extinguish allfibrillatory wavelets. However, this does not happen because atrialcardiac tissue is not homogenous. As documented in the field,electrophysiological properties such as conduction velocity,excitability, and refractory period have spatial inhomogeneity. E.g.,see M. Wijffels, et al., Circulation, vol. 92, No. 7, October 1995, pp.1954-1968. Thus, when a certain atrial region is paced at a certain rateother atrial regions with longer refractory periods cannot follow thehigher pacing rate in a 1:1 manner. This results in conduction blocks.The atrial regions with longer refractory periods will continue at aslower rate than the rate of entrainment. The resulting asynchrony inactivation will perpetuate fibrillation. Accordingly, these types ofatrial inhomogeneities have permitted only a very limited area ofcapture to be achieved by prior uses of a single pacing site.

Although not directed to atrial defibrillation therapy per se, U.S. Pat.No. 5,161,528 teaches a method and apparatus for defibrillating a mammalwith reduced energy requirements in which the heart's fibrillation cyclelength is determined and then multiple sub-threshold bursts ofelectrical current are administered to the mammal with the burstintervals based as a percentage of the heart's fibrillation cycle.Preferably, the timing of successive bursts is set to be about 75% to85% of the fibrillation cycle length. The sub-threshold shocks areinsufficient by themselves to terminate depolarization wave propagation,but can be used to alter the timing of the depolarization wavefrontalong its re-entrant pathways and thereby constrain the depolarizationwavefront. While U.S. Pat. No. 5,161,528 broadly suggests use of aplurality of electrodes to concurrently deliver shocks through multipledifferent pathways, at the same or different times, the patent clarifiesin the experiments described therein how the ventricular defibrillationis achieved using a determination of an average fibrillation cyclelength value derived from a plurality of electrocardiogram measurements,and that the calculated average fibrillation cycle length is used as thebasis for setting the electrical burst rate applied. The ventriculardefibrillation therapy taught by U.S. Pat. No. 5,161,528 is nottranslatable to atrial defibrillation because the shocks deliveredpursuant to the therapy of the >528 patent reference require relativelylarge amounts of electrical energy, viz. 2.7 joules and even muchhigher, which is well outside the above-identified acceptable comfortzone of a typical conscious chronic patient in need of atrialdefibrillation.

From the foregoing, it can be appreciated that there presently exists aneed for a modality of delivering cardiac therapy that reduces atrialdefibrillation thresholds to eliminate or at least significantly reducethe pain and discomfort to a patient undergoing atrial defibrillationtreatment.

It is another object of this invention to provide a method forterminating atrial fibrillation or at least to improve atrialdefibrillation efficacy by bringing large regions of atrial tissue intophase-lock via a regimen of pacing level pulses alone. The above andother objects, benefits and advantages are achieved by the presentinvention as described herein.

SUMMARY OF THE INVENTION

The present invention relates to treatment modalities for atrialarrhythmias in which pacing is used to advantageously effect atrialfibrillation. Atrial defibrillation threshold (ADFT) energy requirementshave been shown to be dramatically reduced or even eliminated on accountof the pacing regimens of this invention. As a result, atrialdefibrillation can be effected in a patient without the need to subjecta patient to negatively perceived electrical stimulations.

The present invention can be understood at several different levels.From the most generalized perspective, the embodiments of the presentinvention commonly share the protocol of first conducting atrial pacingfrom one or more pacing sites in the atrium so as to maximize the extentof phase-locked area of atrial tissue. The instantaneous atrial pacingrate delivered at the pacing site(s) is based on current atrialfibrillation cycle length (AFCL) data sensed in real time. The variouspacing regimens of the present invention can themselves terminate atrialfibrillation, or, at the minimum, they serve to significantly lower theenergy requirements needed in an additional atrial defibrillation (ADF)shock-delivery tier of therapy. For example, after pacing has beenconducted for a short period of time, ADF shocks are then introduced, ifstill needed, to terminate the atrial fibrillation episode.

Several pacing regimen options are encompassed at the incipient pacingtier of therapy in accordance with this invention, while the particularsof the ADF shock tier of therapy are essentially the same regardless ofwhich one of the inventive pacing regimens that it is being used inconjunction with.

In one specific embodiment of this invention, there is a method forterminating atrial fibrillation including a pacing regimen in whichmultisite pacing is conducted in a synchronous manner, whereby thepacing is delivered at each of the multiple pacing sites as anequal-interval train of pulses delivered at a predetermined couplinginterval set proportional to a common atrial fibrillation cycle length(AFCL) value. This pacing regimen brings large regions of fibrillatingatrial tissue into phase-lock via delivery of pacing level pulses alone.Once phase-lock is obtained via such synchronous multisite pacing, anatrial defibrillation shock is delivered, if still necessary, toterminate atrial fibrillation. The selection of the common AFCL used forsetting the pacing rates of the multiple pacing sites preferably is setto be equal to the minimum (i.e. shortest in a temporal sense) localAFCL value determined among the sensed local atrial sites. The localAFCL values can be determined by counting the number of depolarizationwavefronts to enter the given atrial site over a selected period timeand then calculating the median or mean AFCL value from thatinformation. This approach is especially useful where different locallysensed AFCL values vary significantly from one another.

Generally speaking, the greater the variance of electrophysiologicalproperties as between the different atrial locations to be paced, themore sensitive the result achieved will be to the manner of choosing thesingle AFCL value for setting the synchronized pacing rate. Forinstance, where the set of local AFCL values are grouped very closelytogether, the choice of the minimum AFCL as the basis for the settingthe pacing rate, i.e., the time intervals between delivery of successivepacing pulses (also referred to herein as the "S1-S1 interval"),commensurately becomes less critical. Also, empirical studies by thepresent inventors have demonstrated that for a special case where atrialsensing is performed from only a single site while multiplesynchronously paced atrial sites are used, that basing the pacingregimen on the AFCL sensed at the Bachmann's Bundle alone is adequate toachieve the stated objectives of this invention.

In a preferred embodiment of this invention using the synchronousmultisite pacing regimen, the synchronized pacing trains are deliveredto the various pacing sites to phase-lock tissue at a uniform S1-S1interval proportionally set as 70-99%, preferably 80-95%, of the minimumAFCL. Next, a defibrillation shock is delivered, if still necessaryafter pacing, to terminate atrial fibrillation at a uniform timeinterval between the last pulse of the pulse train and the specific timethereafter when the ADF shock is delivered (also referred to herein asthe "S1-S2 interval"), as proportionally set as 85-95% of the S1-S1interval.

In another specific embodiment of this invention, there is a method forterminating atrial fibrillation including a pacing regimen in whichmultisite pacing is conducted in an asynchronous manner, whereby thepacing is delivered concurrently to different local sites of the atriumin an independently controlled manner to procure local captures vialocalized pacing therapies. The pacing is delivered at the multiplepaced sites as an equal-interval train of pulses delivered at apredetermined coupling interval set proportional to the locallydetermined atrial fibrillation cycle length (AFCL) value determined inreal time. This pacing regimen also brings large regions of fibrillatingatrial tissue into phase-lock via delivery of pacing level pulses alone.Once local phase-lock is obtained via such asynchronous multisitepacing, an atrial defibrillation shock is delivered, if still necessaryto terminate atrial fibrillation.

In a preferred embodiment of this invention using the asynchronousmultisite pacing regimen, the local pacing trains are delivered to thevarious pacing sites to phase-lock tissue at S1-S1 intervals setproportionally as 70-99%, preferably 80-95%, of the local AFCL. Next, adefibrillation shock is delivered, if still necessary after pacing, toterminate atrial fibrillation at a uniform S 1-S2 intervalproportionally set as 85-95% of the minimum S1-S1 interval.

In a further optional embodiment involving the asynchronous pacingregimen, once independent local phase-lock is achieved, regional capturemeasures can be performed using a synchronized pacing regimen thatinvolves coordination of pulsing regimens in neighboring capturedregions of tissues to maximize the capture area.

In yet another specific embodiment of this invention, pacing of theatrium is conducted from a single pacing site that is adjacent to thelow potential gradient region of atrial tissue, defined infra, with agoal being to eventually entrain all atrial tissue by pacing alone. Inthis embodiment, the S1-S1 interval is preferably set as a certainproportion, generally 70-99%, and preferably 80-95%, of the sensed AFCLof minimum value. Next, a defibrillation shock is delivered, if stillnecessary after the single site pacing, to terminate atrial fibrillationat a uniform S1-S2 interval proportionally set as 85-95% of the S1-S1interval.

In another embodiment, this invention encompasses a cardiac therapyapparatus, and preferably an implantable cardioverter defibrillator(ICD) device, capable of implementing the aforesaid pacing and ADF shocktherapies.

As compared to atrial defibrillation threshold (ADFT) without phase-lockbeing provided via pacing according to this invention, the ADFT withphase-lock provided via pacing in accordance with this invention issignificantly lowered to greatly diminish, if not eliminate, anydiscomfort or pain to the patient.

For purposes of this application, the following terms have the indicatedmeanings:

Capture: means pacing of the atria from one or more sites where eachpacing stimulus results in a repeatable activation pattern of the entireatrium. The wavefronts originate at the pacing electrodes and the phaserelationship between the pacing stimulus and the activation of eachsection of the atrial tissue remains constant throughout the pacingevent.

Entrainment: means the same as capture.

Regional capture: pacing of the atrium from one or more sites where thestimulus results in wavefronts which depolarize only a portion of themyocardium surrounding the electrode or electrodes. The spatial extentof the depolarization caused by the pacing stimulus changes from beat tobeat and occasionally may result in almost no propagated response. Thewavefronts activating the captured region originate at the pacingelectrode. The phase relationship remains constant between the pacingstimulus and activation of each section of myocardium within the regionthat is captured.

Phase-locking: pacing of the atrium from one or more sites which resultsin wavefronts that appear to be constant in phase with the pacingstimulus but where there does not appear to be a cause and effectrelationship. That is, the wavefronts do not appear to originate at thepacing sites and small changes in phase between the pacing stimulus andthe activation of each section of a region occur over time. As aqualification, where EGM data on the atrium is limited, it is oftendifficult to differentiate between phase-locking and capture, as definedherein, and, for those cases, phase-locking terminology is used hereinto refer to both capture and phase-locking.

Atrial Defibrillation Threshold or ADFT: The minimum amount ofelectrical energy required to defibrillate a fibrillating atrium of apatient.

Atrial Fibrillation Cycle Length or AFCL: the timing required betweentwo consecutive depolarization wavefronts to traverse the same locationis the atrial fibrillation cycle length (AFCL).

Pacing Rate: also referred to herein as the S1-S1 interval, meaning thetime intervals between delivery of successive pacing pulses.

Coupling Interval for Pacing Initiation or CIPI: means the time delaybetween the last local activation sensed, as the trigger, and the startthereafter of the first pulse of the pacing train.

Coupling Interval for Defibrillation Shock or CIDS: also referred toherein as the S1-S2 interval, meaning the time interval between the lastpulse of a pulse train and the specific time thereafter when an ADFshock, i.e., the defibrillation trigger, is delivered.

Low potential gradient region of atrial tissue: the region in the atriumwhere the electric field lines generated by the current flowing betweena pair of defibrillation electrodes positioned in the atrium are theleast densely spaced. The location of this region can vary to the extentthat the potential gradients generated by a defibrillation shock dependupon the particular lead configuration of the defibrillation electrodesin the atrium, the tissue conductivities, and torso geometry. The lowpotential gradient region can be located by measurement or intuitively.

BRIEF DESCRIPTION OF THE DRAWINGS

These and various other features and aspects of the present inventionwill be readily understood with reference to the following detaileddescription taken in conjunction with the accompanying drawings, inwhich like or similar numbers are used throughout, and in which:

FIG. 1 is a waveform diagram of an EGM showing an atrial fibrillationcycle length (AFCL) and the refractory period and excitable gap thereof.

FIG. 2 is a flow chart illustrating the treatment method of the presentinvention in which a multisite pacing regimen is used.

FIG. 3 is a detailed flow chart description of the SPace FlowChart boxesdepicted in FIG. 2.

FIG. 4 is a representative pacing stimulation pattern for synchronousmultisite pacing according to an embodiment of this invention showingthe relationship of CIPI to a local EGM for a given sensing/pacing site.

FIG. 5 depicts representative pacing stimulation patterns forsynchronous multisite pacing according to an embodiment of thisinvention. In this and all other Figures herein illustrating pacingstimulation patterns, the ordinate axis indicates the relativeelectrical stimulus intensity and the abscissa axis indicates the timeperiod.

FIG. 6 is a representative pacing stimulation pattern for synchronousmultisite pacing according to an embodiment of this invention showingthe transition from pacing therapy to defibrillation shock therapy.

FIG. 7 is a detailed flow chart description of the APace FlowChart boxesdepicted in FIG. 2 involving asynchronous (local) multisite pacing.

FIG. 8 shows two representative pacing stimulation patterns forasynchronous multisite pacing according to an embodiment of thisinvention and the simultaneous termination of the pulse trains.

FIG. 9 shows two representative pacing stimulation patterns forasynchronous multisite pacing according to multisite pacing pathway AC@in FIG. 2.

FIG. 10 is a diagram showing an embodiment of the invention forachieving regional atrial capture by coordinating the pulsing ofneighboring locally captured atrial sites according to multisite pacingpathway "C" in FIG. 2.

FIG. 11 is a flow chart illustrating the treatment method of the presentinvention in which a single site is used for pacing.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

When heart cells are activated, the electrical polarization caused bythe normal voltage difference of about 90 mV between the inside andoutside of the cells collapses and the heart tissue is said to"depolarize." Depolarized heart tissue which has not been given adequatetime to re-establish its normal voltage difference and will not producea new activation in response to a further intrinsic or extrinsicelectrical stimulus is referred to as refractory tissue. Afterdepolarization, heart cells begin to re-establish the normal voltagedifference ("repolarization"). Tissue which has been afforded anadequate length of time to re-establish a sufficiently large voltagedifference to once again become susceptible to depolarization is nolonger refractory. The time interval which is required after a cell hasbeen depolarized until it is again nonrefractory is called therefractory period. In a fibrillating heart, depolarization wavefrontsmove through the myocardium along re-entrant pathways in a chaoticmanner. The time period required for a given depolarization wavefront totraverse and complete a circuit along some re-entrant pathway in theatrium is the atrial fibrillation cycle length (AFCL). The periodfollowing an activation when tissue becomes non-refractory again isreferred to as the "excitable gap." As figuratively illustrated in FIG.1, the excitable gap follows the refractory period of the AFCL, asindicated between the successive activations A1 and A2.

Moreover, based on high density atrial sensing mapping performed by thepresent inventors, there generally can be three different patterns ofAF, which are categorized as follows:

Type I AF where the surface of each atrium is activated by a singlewavefront propagating uniformly or with only minor local conductiondelays not disturbing the main course of the activation wave;

Type II AF where the are activations by a single wavefront showing majorconduction delay or by two different activation waves separated by aline of functional block; and

Type III AF where an atrium is activated by multiple wavefronts (>2)separated by multiple lines of conduction block or by areas of slowconduction. When the variability in local sensed AFCL is low, it is morelikely to be Type I AF, whereas if the variability in local sensed AFCLis high, it is more likely to be Type III AF.

In the threshold tier of the atrial defibrillation therapy of thisinvention, large areas of atrial tissue are phase-locked by pacing at apacing rate(s) proportional to the AFCL data as determined in real time.Based on the sensed AFCL data, the pacing is controlled in real timesuch that the Coupling Interval for Pacing Initiation (or CIPI), i.e.,the time between the last activation sensed and the delivery of thefirst pulse of the pulse train, is selected so as to fall in theexcitable gap. Thus, the CIPI is selected to be sufficiently long toensure that the myocardial tissue is well out of refractoriness so thatthe local regions to be paced can be easily excited by the first pulseof the respective pacing train, whereby the resulting wavefront spreadsout rapidly at each pacing site to capture a large portion of thesurrounding tissue. On the other hand, the coupling interval is alsoselected to be shorter than the AFCL so that the extrinsic electricalpacing stimulus induced pre-emptively activates and depolarizes thetissue before the next fibrillation wavefront is expected to invade thearea. Since depolarization wavefronts associated with fibrillationrequire repolarized tissue to propagate, depolarization wavefronts canbe constrained in this manner. This provides the phase-lock of thetissues surrounding each pacing site. Once initiated, the pacing traincan proceed according to several different regimens within the scope ofthis invention, including: (a) synchronous pacing from multiple atrialsites, (b) asynchronous or local pacing from multiple atrial sites, (c)single site pacing, or (d) a combination of the aforesaid pacingregimens (a) and (b).

As a secondary tier (in time) of the ADF therapy, after the delivery ofpacing effective to provide the aforesaid large-scale phase-lock of theatrial tissue, atrial defibrillation shocks (S2) are delivered in timedintervals proportional to the pacing (S1-S1) interval to terminate theatrial fibrillation. This second tier of therapy may not be necessary inall cases, particularly where the pacing achieves such extensivephase-lock of atrial tissue that atrial defibrillation is achieved.

The sensing mechanism useful for collecting electrophysiological data ona fibrillating atrium that is useful for determining local fibrillationcycle lengths according to the principles of this invention includethose that are conventional in the art. Such sensors generally comprisea conventional sensing electrode or electrodes, positioned in or on theheart in locations suitable for monitoring the electrical activityassociated with a fibrillating heart and producing analogelectrocardiograms (EGM) signals in response thereto; an amplifier foramplifying the EGM signals; a waveform digitization means for digitizingthe EGM signals to produce digital electrocardiogram (EGM) signals; andsignal processing means that process the EGM data in accordance with thetherapy delivery algorithm (implemented in software) embraced by thisinvention. For example, the signal processing means can be amicroprocessor used for diagnosing whether fibrillation is present,determining the fibrillation cycle length(s), calculating theappropriate pacing and/or shock rates needed based on the AFCL data, andconfirming whether fibrillation is terminated upon treatment. Thedetermination of the fibrillation cycle length can be done by countingthe number of depolarization wavefronts to enter the atrial site beingsensed over a fixed period time, e.g., several seconds, and thencalculating the median or mean AFCL value from that information.Preferably, the fibrillation cycle length is determined for eachfibrillation event of a given patient with continuous monitoring by thesensing electrodes so that the electrical stimulus regimen can be setaccording to the algorithm described herein in a real time mode, asopposed to using preselected fixed intervals. It is also possible toadjust the electrical stimulus therapy in real time during treatment aschanges in the fibrillation cycle lengths are identified. The inventionwill be even better understood from the details provided below ofseveral preferred embodiments of the invention.

ADF Therapy Including Multisite Synchronous Pacing:

Referring to pacing therapy pathway "A" indicated in FIG. 2, multisiteatrial pacing can be performed in a synchronous fashion in conjunctionwith atrial defibrillation shocks, if needed, to terminate atrialfibrillation in a heart. In this modality of the invention, themultisite pacing tier of this therapy mode involves use of pacing trainsat multiple atrial sites at a synchronized pacing rate to phase-locklarge portions of fibrillating atrial tissue. In this pacing scenario,the activation profile is sensed for a brief period of time, e.g., overseveral seconds (e.g., 1-2 seconds), at the plurality of atrial siteswhere pacing is to be delivered. The median or arithmetic mean AFCLvalue is calculated from the data collected at each sensed local site.

As indicated in FIG. 3, the minimum AFCL value among this set of localAFCL data is identified and used as the basis for setting the pacingparameters. It typically is preferable to calculate the median AFCL foreach sensed local site to better attenuate any possible extreme outlyingdata points, although the mean AFCL values are also acceptable in mostcases. The coupling interval for pacing initiation (CIPI) for all pacingsites is uniformly set as a value in an "x-y%" range equal toapproximately 70-99%, preferably approximately 80-95%, with respect tothe determined minimum atrial fibrillation cycle length. FIG. 4 shows arepresentative local EGM (41) for one of a multiplicity of atrial pacingsites used under this embodiment in which the first pulse (42) of thepacing train (43) delivered at that site falls at a specific time afterthe last sensed local activation (α₄), following previous local sensedactivations α₁ to α₃, based on a CIPI value that is calculated in theabove-described manner.

A uniform CIPI is set for all the pacing sites. Namely, the common CIPIvalue for pacing is set as a percentage value in the range of "x-y%" ofthe minimum sensed AFCL. If the variability of the local sensed AFCLs ishigh, a setting of the CIPI (and S1-S1 pacing rate) in the 70-99% rangethat is closer to 70% of the minimum local sensed AFCL is morefavorable, while if the variability of the local AFCLs is low, a settingfor the CIPI (and S1-S1 pacing rate) in the 70-99% range that is closerto 99% of minimum AFCL is more favorable. This is because it ideally isdesired to deliver the pacing pulse just before the next fibrillatorywavefront is expected to invade. When the variability of the local AFCLsis low, it is likely that the fibrillatory wavefronts are fewer innumber and more organized. The probability that the next wavefront willinvade in a manner similar to the last few wavefronts is high. Thus, itis desired to set CIPI to be closer to 99% of minimum AFCL. When thevariability of local AFCLs is high, it is likely that the fibrillatorywavefronts are more in number and less organized. In order to beconfident that the next fibrillatory wavefront does not invade justbefore the delivery of the first pacing pulse, it is necessary to setCIPI closer to 70% of minimum AFCL.

As indicated in FIG. 5, for four illustrated pacing sites, PS₁ to PS₄,the pacing tier of this therapy preferably involves burst pacing with atrain of pulses with identical coupling intervals, i.e., S1-S1intervals, being delivered at each of the multiple pacing sites. Asindicated in FIG. 5, the sensed atrial sites are paced synchronouslyfrom pacing sites PS₁ to PS₄ at a uniform S1-S1 value of "x_(p) "milliseconds set at approximately 70-99%, preferably approximately80-95%, of the determined minimum AFCL. E.g., where the minimum AFCL isdetermined to be 100 milliseconds, then S1-S1 could be set to be 80milliseconds, among other values within the above-prescribed ranges.While FIG. 5 indicates a phase delay between the various pulse trains,i.e., phase delays PD1-2, PD2-3, and PD3-4, it is also possible toproceed without phase delay. In any event, the patient's physician,e.g., an electrophysiologist, can specify a phase delay between thepulse trains being delivered. For example, if there are four activepacing sites, the patient's physician can specify that a first pulse(P₁) be delivered by a first active electrode, then 5 milliseconds latera second pulse (P₂) be delivered by a second active electrode, then 10milliseconds later a third pulse (P₃) be delivered by a third activeelectrode, and 0 milliseconds later a fourth pulse (P₄) be delivered bythe fourth active electrode, as illustrated in FIG. 5.

Also, during synchronous pacing, i.e., "SPace" in FIGS. 2 and 3, themulti-site pacing system (MPS) can increment or decrement the pacingrate. The rate change can be made either manually during the pacing, orautomatically by the computer. For example, the MPS can deliverincremental pacing starting with a constant given rate and incrementingby a prescribed amount after each pacing pulse.

During pacing, capture verification can be provided. If capture is notverified at all locations, then the S1-S1 interval can be decremented.If capture is verified at all locations, then the S1-S1 interval can beincremented. Also, once capture is verified, a phase delay can beintroduced between different pacing trains.

As an illustration of such phase delay introduction, SPace initially isdelivered with no phase delay during Type I AF using two pacing sites.One site is placed on the right atrial (RA) free wall and one on theleft atrial (LA) free wall. A CIPI of 95% AFCL is used to couple to anactivation on the LA electrode. After approximately 2 seconds of SPacewith zero phase delay, 2 seconds of SPace with 10 msec phase delay isadded with the RA train leading the LA train. This delay is addedbecause during sinus rhythm the RA activates before the LA. In thismanner, phase delay can be provided during pacing from multisites.

It will be understood that this embodiment of the invention is notlimited to any particular plural number of pacing sites. The electricalenergy used may have any suitable waveform commonly known and used inthe art. The pulse delivery electrodes and related energy supply andcontrol systems used can be of any type known in the art, e.g., of anytype commonly used in implantable pacemakers. At each of the activeelectrodes, the characteristics of the pacing pulses can be individuallycontrolled. They can have an amplitude of 0-10V and can be eithermonophasic (anodic or cathodic) or biphasic. Suitable pacing orpacing/sensing electrodes are generally a few square mm in area. Theycan be selected from active fixation type electrodes (e.g., screw-intype) passive fixation type electrodes (e.g., tined types), and orfloating type electrodes. The defibrillation electrodes are a few squarecm in area. They can be selected from standard transvenous activefixation type electrodes (e.g., screw-in type) passive fixation typeelectrodes (e.g., tined types), and floating type electrodes that are afew cm in length (e.g., 3-7 cm) and a few french in diameter (e.g., 2-10F). Configurations of two or more defibrillation electrodes can be used.

In general, each pacing pulse delivered by the pacing electrodes canvary between 0.1 to 10 volts, the duration of each electrical pulse canbe 0.03 to 3 milliseconds, and the energy of each pulse can be in the0.01 to 50 microjoule range. The aforementioned electrical properties ofthe pulses are values suitable for internal administration, such as viaan ICD. External administration would require significantly highervoltage levels than set forth above, as understood in the art.

Each pacing train of pacing therapy pathway A is applied for a durationof approximately 1-10 seconds, typically about 2 seconds. Then asindicated in FIG. 2, pacing is momentarily discontinued to verifywhether defibrillation has been achieved (e.g., by checking for ADF viaatrial sensing and diagnosis at the microprocessor), and, if not, theminimum AFCL is determined again, and the CIPI and S1-S1 interval resetin real time according to the same guidelines described above and thenmultisite pacing under pathway A is renewed based on the most recentAFCL data. This pacing protocol for pathway A is repeated "n" number ofiterations unless defibrillation is verified between successive pacingadministrations under pathway A until a preselected count "x_(c) " isreached, where "x_(c) " is typically set to be about 3-5 times. Theiterative multisite pacing tier of pacing therapy pathway A of thisinvention has been found to phase-lock large regions of the atrium, evenif atrial fibrillation is not terminated. If atrial defibrillation isachieved via the iterative multisite pacing alone under pathway A, thenthe therapy regimen is returned to background ICD atrial sensing fordetection of future defibrillation episodes. Alternatively, if thepacing tier of the therapy per se under pathway A does not defibrillatethe atrium, then the atrial defibrillation therapy adds a second therapytier of defibrillation shock delivery after completing pacing iterationx_(c). Namely, if the multisite pacing under pathway A does not achievedefibrillation after pacing attempt number x_(c) -1 then multisitepacing therapy alone is aborted and the next pacing attempt (i.e.,pacing attempt number x_(c)) adds a defibrillation shock at the end ofthe pacing train.

Referring to FIG. 6, which illustrates pacing trains PT₁ and PT₂ beingdelivered concurrently at two different atrial sites, the couplinginterval for defibrillation shock (CIDS), which is also occasionallyreferred to herein as the "S1-S2 interval," is set within a percentagerange of the S1-S1 interval being used. The timing of the associateddefibrillation trigger (DT) and defibrillation shock (DS) delivery inthis regard are also indicated in FIG. 6. Namely, the S1-S2 interval(CIDS) between the last pacing pulse 61 and DT (and DS) preferablyshould be approximately 85-95%, and more preferably, approximately 90%,of the S1-S1 interval. The desired significant reductions in the ADFTenergy requirements are very sensitive to the S1-S2 interval value, andbecome readily lost as the S1-S2 interval goes below 85% of the S1-S1interval or goes above 95% of the S1-S1 interval. For example, if theS1-S1 interval shown in FIG. 6 is 100 milliseconds for both pulse trainsPT₁ and PT₂ in an ongoing ADF treatment, then the S1-S2 interval (CIDS)preferably would be set to be 85 to 95 milliseconds, e.g., 90milliseconds, to satisfy the above-indicated criterion for selecting theS1-S2 interval (CIDS). As also indicated in FIG. 2, if for some reasonCIDS inadvertently is not enabled, a defibrillation shock will beimmediately added at the end of last pacing train as a default measure.However, to achieve the desired significant reductions in the energylevels for ADFT, the S1-S2 interval should be set in theabove-prescribed ranges. The implementation of CIPI and CIDS can be donevia hardware modifications, software modifications or a combination ofhardware and software modifications.

Once phase-lock is obtained via synchronous multisite pacing asdescribed above, the second tier of the therapy is introduced in which asingle atrial defibrillation (ADF) shock is delivered at the end of thepacing train sufficient to terminate defibrillation. The ADF shock canbe delivered using the same or different electrodes being used forpacing. However, from a practical standpoint, sensing is done withelectrodes separate from the defibrillation electrodes. The ADF shockscan have monophasic or biphasic waveforms. Biphasic truncatedexponential waveforms are preferred.

The ADF shocks are delivered with current supplied at less than 1.0joule, preferably less than 0.5 joule, and more preferably in a range ofabout 0.1 to 0.4 joule, at a delivery voltage of about 80 to 250 volts,with the duration of each ADF shock varying from about 5 to 15milliseconds. Preferably, the aforementioned electrical properties ofthe ADF shocks are values suitable for internal administration, such asvia an ICD. External administration would require significantly highervoltage levels than set forth above, as understood in the art. Virtuallyall currently available ICDs have the required power supply capacity tomeet that requirement of the present invention. Also, virtually allcurrently available ICDs can be configured by one of ordinary skill inthe art to provide the hybrid therapy with AFCL determination and pacingfrom a single site or multiple sites in accordance with the presentinvention. Some ICDs are currently available which should be able withdual pace/sense channels to be used such that they sense AFCLs from bothchannels and facilitate many forms of multisite pacing. Multisite pacingfrom two or more sites can be achieved by coupling together two or moreelectrodes to the same pace channel.

Compared to ADF without phase-lock, experimental studies summarizedherein have shown that the ADFT energy required to terminatefibrillation with phase-lock pursuant to this invention is significantlylower, viz. about 30 to 70% lower in power requirements, as demonstratedby studies in sheep with chronic AF. At the 70% reduction level, only a0.2 joule ADF shock has been needed to achieve atrial defibrillation.

While not desiring to be bound to any particular theory at this time, itnonetheless is thought the maximization of the entrainment orphase-locked area by the above-described synchronous pacing regimenresults in increased organization, a reduced number of wavefronts, andlesser dispersion in refractoriness. All of these beneficial results aidin reducing the amount of energy otherwise required to re-synchronizethe atrial tissue and thereby reduce the ADFT.

In implementing this embodiment of multisite synchronous pacing, it willbe appreciated that certain variations are possible within the scope ofthe invention. For instance, the number of sensing and pacing sites neednot be identical for all cases. By way of illustration, in treatingsheep with chronic atrial fibrillation, a median AFCL, i.e., the AFCLcalculated as the median value of the readings taken at the given atrialsite, for the right atrium (RA) has been measured to be about 138milliseconds, and 122 milliseconds for the left atrium (LA). If theAFCLs are obtained from the LA alone and pacing is being performed onboth the RA and LA, then the S1-S1 interval should be set closer to 95%rather than 80% of the median AFCL, such that the preferred x-y% valuefor the S1-S1 interval is 85-95% in that pacing scenario. If AFCL(s) aredetermined instead from the RA alone and pacing is performed on both theRA and LA, then the S1-S1 interval needs to be closer to 80% rather than95% of the median AFCL, such that the preferred x-y% value for the S1-S1interval is 80-90% in that pacing scenario. As another alternative, ifAFCLs are obtained from both the RA and the LA, then the S1-S1 intervalcan be set to be 80-95% of the median AFCL.

As other possible alternative methods for setting the uniform multisiteS1-S1 interval, it also will be understood that the maximum or othernon-minimum local AFCL value determined among the sensed pacing sitescould be equally useful as the chosen AFCL basis for calculating theS1-S1 interval, namely where the various local AFCL values are veryclosely grouped together in numerical terms, i.e., where standarddeviation o is extremely small. In yet another possible alternative toreal time sensing and determining the minimum local AFCL value used asthe basis for setting the common S1-S1 interval, if a patient is treatedfor which an established history has been developed insofar asrepetitive electrophysiological characteristics associated with variousatrial sites for pacing, then the AFCL could be pre-set as a fixedvalue. Also, the present investigators have determined that if a singlesensing site is located at the Bachmann's Bundle, then the mean ormedian AFCL sensed there can be used as the basis for setting theuniform S1-S1 interval at multiple pacing sites of the atrium insynchronous pacing. That is, using the median AFCL determined at theBachmann's Bundle for setting the CIPI and the S1-S1 interval as apercentage thereof, viz., 70-99% and preferably 80-95% of the medianAFCL sensed at the Bachmann's Bundle for both parameters, permitssignificant reductions in ADFTs to be achieved. Similarly, it also iscontemplated within the scope of this invention to use the median AFCLsensed at one of the septum, the distal coronary sinus, or the rightatrial free wall, as the basis for setting the CIPI and a uniform S1-S1interval at multiple pacing sites of the atrium in synchronous pacing asa percentage thereof, viz., 70-99% and preferably 80-95%, of the medianAFCL sensed at one of these atrial locations.

Also, in initiating the pacing, the trigger can be either given manuallyby the patient's physician (during device programming), or the triggercan be generated automatically as soon as an activation is sensed atcertain electrodes. As an example. for automatic triggering, if thereare two electrodes, the triggering-active electrode can be specified bythe patient's physician to be either active electrode or the activeelectrode associated with shorter or longer AFCL. A longer AFCL isusually easier to phase-lock than a shorter AFCL. CIPI improvesprobability of phase-lock so the triggering-active electrode has ahigher probability of phase-locking. Usually the electrode with shorterAFCL is made triggering-active. Another triggering option is to wait foractivations to be sensed at all active-electrodes within, for example,10 msec of each other. Once this occurs, with respect to that activationsensed at the triggering electrode, the pacing is initiated.

Similarly, at the end of the pacing train, the MPS can provide adefibrillation trigger for the delivery of the ADF therapy. Thepatient's physician can either enable or disable the defibrillationtrigger (during device programming). Also, where the defibrillationtrigger follows SPace, the CIDS can be set as a percentage of the S1-S1interval as described above, or alternatively, the CIDS can be set to apreselected value, such as where the patient's atrial fibrillationhistory is well-established.

AF Therapy Based Upon Multisite Asynchronous (Local) Pacing:

In a second modality of this invention, which is indicated as proceedingunder either one of therapy pathways "B" or "C" in FIG. 2, asynchronouspacing (designated as "APace") is concurrently performed at a locallevel at a plurality of pacing sites using local sensing andmeasurements of local AFCLs in real time that, in turn, are used to setthe local pacing rate at each given pacing site, independent of thepacing rate used at any other local pacing site.

This multisite local asynchronous pacing embodiment directly addressesand accommodates the fact that the atrial fibrillation cycle length(AFCL) can vary from location to location and also for a given atrialtissue location. Namely, the local pacing rate at each pacing site isset to be a prescribed percentage of the sensed local AFCL such that thefirst pulse of the pacing train that is delivered at each local pacingsite falls in the local excitable gap for the given local tissue, i.e.,the period of time after the local refractory period and before the nextfibrillatory wavefront is expected to return and otherwise depolarizethe local region again. As different regions of the atrium can andtypically do have different AFCLs and associated local refractoryperiods, for this pacing regimen, the pacing rate at a given location ismade proportional to the local electrophysiological properties (viz.,AFCL or refractory period) irrespective of the other pacing rates beingconcurrently used at other atrial locations. This pacing regimen iscontinued at least until phase-lock is confirmed for the local areasbeing paced, e.g., for one or several seconds. Some coordination ofpacing rates in neighboring captured areas is possible at that point tomaximize the region of capture, as indicated in pacing therapy pathway"C" in FIG. 2.

Referring to FIG. 7, the variables for setting the "APace" pacing trainunder this second pacing scenario using independently set pacing ratesfor a multiplicity of pacing sites are as follows. To produce the pacingpattern needed to maximize the area of phase-lock, the coupling intervalfor pacing initiation (CIPI) between the last local activation sensedand the first pulse of the local pacing train should be set to be an"x-y%" range of approximately 70 to 99%, more preferably 80-95%, of thedetermined minimum atrial fibrillation cycle length (AFCL) among thesensed sites where pacing is to be delivered. This manner of selectingCIPI ensures that the first pulse of the local pacing trains are eachdelivered outside the local refractory period of the local tissue. Ifthe variability in local AFCLs is small, the CIPI is set closer to 99%of the minimum local AFCL, while, if the local AFCLs are high invariability, the CIPI is set closer to 70% of the minimum local AFCL.Then, the next local activation is awaited, and once sensed, each localpacing train is initiated using the above-determined CIPI.

Before initiating pacing, it is preferred to monitor the local AFCL fora few seconds, e.g., about two seconds, then determine the variousmedian local AFCLs (P50) and the variability in the local AFCLs byconventional statistical calculations. The median AFCL measured at eachpacing site preferably is used to determine the minimum AFCL, althoughuse of arithmetic mean local AFCL values also could be employed.

In setting the local pacing rates, i.e., the local S1-S1 intervals, therate of each local pacing train should be set to be an "x-y%" range ofapproximately 70 to 99%, more preferably 80-95%, of the determinedrelated local AFCL. For instance, if the minimum local AFCL among theplurality of pacing sites being sensed is determined to be 100milliseconds (msec), then once a local activation is sensed at eachlocal pacing site, the local pacing train should be initiated 70 to 99msec thereafter, preferably 80-95 msec thereafter, and then the localS1-S1 interval rate should be set to be 70 to 99 msec, preferably 80-95msec, for each local pacing site. If the CIPI were set as 30-69% of theminimum AFCL, the pulse would produce no noticeable effect on thefibrillatory wavefronts because the local tissue cannot be extrinsicallyactivated while still in a refractory period. Similarly, if the CIPIwere set greater than 100% of the minimum AFCL, the excitable gap willbe missed altogether.

The preferred percentage of the local AFCL to use in setting the localpacing rates (within the 70-99% range) should factor in the variabilityof the local sensed AFCLs. If the variability of the local AFCL for agiven pacing site is high, a setting for the local pacing rate closer to70% of the local AFCL is more favorable, while if the variability of thelocal AFCL is low, a setting for the local pacing rate closer to 99% ofthe local AFCL is more favorable.

For instance, as illustrated in FIG. 8 for two pulse trains PT_(a) andPT_(b) for two different atrial pacing sites the respective S1-S1intervals, viz., AS₁ -S₁ and BS₁ -S₁, are managed independent from eachother in this embodiment for the different pacing sites up until thelast pulse in the respective pacing trains which both are delivered atthe same time (tt). For instance, AS₁ -S₁ might be 140 millisecondswhile BS₁ -S₁ is 100 milliseconds, depending on the related local AFCLvalues of the two pacing sites. As alluded to above, where localmultisite pacing is delivered, the MPS delivers the pulse trains in amanner such that the last pulse at each of the sites is delivered at thesame instant (tt), as illustrated in FIG. 8. The simultaneous deliveryof the last pulses is executed by having the microprocessor calculatethe next time the pulses will converge and terminating pulsing afterthat set of simultaneous pulses is delivered.

Under therapy pathway "B" in FIG. 2, after each asynchronous localpacing train ("APace") is delivered for a duration of approximately 1-10seconds, typically about 2 seconds. Then, as indicated in FIG. 2, pacingis momentarily discontinued to verify whether defibrillation has beenachieved (e.g., by checking for ADF via atrial sensing and diagnosis atthe microprocessor), and, if not, the minimum AFCL is determined again,the CIPI and local S1-S1 intervals reset in real time according to thesame guidelines described above and then the multisite pacing therapy ofpathway B is renewed based on the most recent local AFCL data. Thispacing protocol of pathway B is repeated "n" number of iterations unlessdefibrillation is verified between successive pacing administrationsunder pathway B until a preselected count "x_(c) " is reached, where"x_(c) " is typically set to be about 3-5 times. The iterative multisitepacing tier under pacing therapy pathway B of this invention also hasbeen found to phase-lock large regions of the atrium, even if atrialfibrillation is not terminated. If atrial defibrillation is achieved viathe iterative multisite pacing alone under pacing therapy pathway B,then the therapy regimen is returned to background ICD atrial sensingfor detection of future defibrillation episodes.

Alternatively, if the pacing tier of the therapy per se under pathway Bdoes not defibrillate the atrium, then the atrial defibrillation therapyadds a second therapy tier of defibrillation shock delivery aftercompleting pacing iteration x_(c). Namely, if the multisite pacing underpathway B does not achieve defibrillation after pacing attempt numberx_(c) -1, then multisite pacing therapy alone is aborted and the nextpacing attempt (i.e., pacing attempt number x_(c)) adds a defibrillationshock at the end of the pacing train.

Alternatively, as indicated under therapy pathway "C" in FIG. 2, tofurther enhance the asynchronous pacing mode of the invention involvingsuch multisite local pacing, the size of the phase-lock area of atrialtissues can be maximized by coordinating the local pacing ratesaccording to additional aspects of this invention. For instance, oncecontrol (i.e., phase-lock) is obtained at two neighboring atrial regionsvia an "APace" stimulation pattern, each being paced at ratesproportional to the local electrophysiological properties, it is thenpreferable to control both regions from a single pacing site. Toaccomplish this, once control (i.e., phase-lock) is obtained atneighboring regions, there will be instances when both pacing pulses areapplied simultaneously even though different local AFCLs are involved.

In this embodiment, and as illustrated in FIG. 9, multisite pacing fromtwo different atrial locations is performed in an "APace" mode of pacingfor a prescribed duration, e.g., about two seconds, with delivery of thetwo pulse trains PT_(aa) and PT_(bb),then a transition is made at time(t) to a "SPace" mode of pacing after the last pulses of the "APace"mode are simultaneously delivered as described above. For instance, theS1-S1 interval (aS₁ -S₁) for PT_(aa) could be 60 msec while the S1-S1interval (bS₁ -S₁) for PT_(bb) could be 100 msec during the APace mode,then the SPace mode could be applied using a phase delay (pd1-2) betweenthe two pulse trains while using a common S1-S1 interval (cS₁ -S₁) of 60msec. Following this, any one of several approaches can be taken tocoordinate the pulse rates from the neighboring regions in asynchronized manner to maximize the overall area of tissue brought intophase-lock.

As one technique for coordinating the pulse rates of neighboringcaptured areas of tissue, pacing from the slower of the two sites can behalted, and the faster pacing site is used to control the combinedregions.

As another technique, the pulse rate at the slower of the two sites canbe increased to be equal to that at the faster of the two sites. Thesetwo sites then can be made to pace sequentially such that the pacingpulses from the two regions are applied in a sequential manner wheretime lags between consecutive pacing sites are set proportional to theconduction time between the consecutive pacing sites so as to increasethe area of capture. One way of accomplishing this result is shown inFIG. 10, where the dotted lines show activation fronts originating frompacing site AA while the dashed lines show activation fronts originatingfrom pacing site BB. The pacing pulse from site BB is applied when theactivation front originating from site AA has approached close to siteBB. The area enclosed by the dotted lines is rendered under the controlof the pulses emanating from site AA, while the area enclosed by thedashed lines is left under the control of the pulses from site BB. Ifthe first pacing site AA was present by itself during AF, for sake ofdiscussion only, it might control a circular epicardial region of 3-5 cmin diameter. Now, the second pacing site BB is introduced and selectedto be near the border zone of control by the first pacing site AA. Ifthere is such a second pacing site BB, and the first pacing site AA weredelivering pacing pulses at the same instant, the respective wavefrontsemanating from the two neighboring pacing sites would collide. Instead,and per an embodiment of this invention, if the second pacing site BB iscontrolled so as to wait until the wavefront from the first pacing siteAA approaches it and then delivers a pacing pulse, then the direction ofthe resulting propagation will continue in a direction that is similarto the direction of the vector connecting the first to the second pacingsite. By properly selecting the locations of these two pacing sites AAand BB in this manner, the direction of propagation can be controlled asdesired. For instance, the direction can be made to be similar to thatseen during normal sinus rhythm. Moreover, the sequential pacing regimendescribed above using two pacing sites can be extended to more than twopacing sites. If sufficient tissue is controlled, the atrial arrhythmiawill either terminate or the improved organization of the wavefrontswill permit reduction in ADFTs.

The sequential "SPace" subtier of therapy pathway "C" in FIG. 2 isgenerally performed for the time needed to enlarge the capture area,typically about 1-10 seconds. In any event, as indicated in FIG. 2,after adding the sequential "SPace" subtier of therapy to the precedingAPace subtier of pacing therapy pathway "C", the pacing is momentarilydiscontinued to verify whether defibrillation has been achieved (e.g.,by checking for ADF via atrial sensing and diagnosis at themicroprocessor), and, if not, the minimum AFCL is re-acquired and theCIPI and local S1-S1 intervals reset in real time according to the sameguidelines described above and then multisite pacing through therapypathway C is repeated based on the most recent AFCL data. As with pacingtherapy pathways A and B, this pacing protocol under pathway C isrepeated "n" number of iterations unless defibrillation is verifiedbetween successive pacing administrations under pathway C until apreselected count "x_(c) " is reached, where "X_(c) " is typically setto be about 3-5 times. If atrial defibrillation is achieved via theiterative multisite pacing alone under pacing therapy pathway C, thenthe therapy regimen is returned to background ICD atrial sensing fordetection of future defibrillation episodes. Alternatively, if thepacing tier of the therapy per se does not defibrillate the atrium, thenthe atrial defibrillation therapy adds the second therapy tier ofdefibrillation shock delivery after completing pacing iteration x_(c).Namely, if the multisite pacing pursuant to pacing therapy pathway Cdoes not achieve defibrillation after pacing attempt number x_(c) -1then multisite pacing therapy alone under pathway C is aborted and thenext pacing attempt (i.e., pacing attempt number x_(c)) adds adefibrillation shock at the end of the pacing train.

If ADF shocks are necessary to achieve atrial defibrillation afterproceeding through therapy pathway "B" or "C", the protocol forintroducing the ADF shocks is generally the same as that described abovefor multisite synchronous pacing with ADF shocks, and reference is madethereto. When enabled, the delay between the last pacing pulse and thedefibrillation trigger is again called the Coupling Interval forDefibrillation Shock (CIDS).

If the defibrillation trigger follows SPace, or Apace, or APace plusSPace, CIDS can be set by the user to be a percentage of the AFCL fromone of the active electrodes. Alternatively, CIDS can be set as aspecified duration, such as where the patient's history iswell-established. For example, if there are two electrodes, delay can bespecified by the patient's physician (e.g., during device programming)to a percentage of the AFCL at either active electrode or as apercentage of the AFCL at the electrode having a shorter or longer AFCL.

A noteworthy difference between asynchronous multisite pacing versussynchronous multisite pacing, however, is that the setting of the S1-S2interval rate is slightly more complicated with asynchronous multisitepacing because this modality of therapy usually results in a pluralityof different local S1-S1 pacing intervals being involved to achievephase-lock in large combined regions of atrial tissues.

Namely, in order to set the S1-S2 interval, AFCLs are measured from eachactive electrode. The AFCL at the electrode with the maximum AFCL isdesignated AFCL_(max) and the AFCL at the electrode with the minimumAFCL is designated AFCL_(min). In an S1-S2 calculation option 1, theS1-S2 interval is set to be at x-y% of AFCL_(min) where x-y% is anumerical value of 70-99% as described above. In a sequential pacingoption, i.e., therapy proceeding through therapy pathway "C" in FIG. 2,at any pacing site, the S1-S2 interval is set to be within x-y% of thelocal AFCL (upon which the local S1-S2 depends). The followinginequalities must be met: x*AFCL_(min) <S1-S2<y*AFCL_(min) andx*AFCL_(max) <S1-S2<y*AFCL_(max), and both of the above conditions aresatisfied if x*AFCL_(max) <S1-S2<y*AFCL_(min). It follows that an S1-S2interval satisfying the above condition exists only if AFCL_(max)/AFCL_(min) <y/x. If the above condition is not satisfied, the routinereturns to measuring AFCLs. Otherwise, the S1-S2 interval is set to be(AFCL_(max) /AFCL_(min))x-y% of AFCL_(min).

The sensors, active electrodes, and signal processing hardware used topractice the multisite pacing embodiment is generally the same hardwaredescribed above in connection with the synchronous multisite pacingembodiment. It will be understood that the control programming willdiffer between the two embodiments to reflect the different algorithmsdescribed herein used to calculate the S1-S1 and S1-S2 parameters.

Epicardial atrial mapping studies performed by the present investigatorson sheep with chronic AF where treated pursuant to the above-describedasynchronous multisite pacing regimen have demonstrated consistentcapture of local tissue with progressive enlargement in the area ofentrainment by a progressive shift in the collision point between thepaced activation front and the fibrillatory wavefronts. The area ofenlargement can extend from a few centimeters in diameter to an entireatrium. This result increases the likelihood of achieving atrialdefibrillation and restoring sinus rhythm without pain by using pacinglevel pulses alone having very low energy, or, if necessary, inconjunction with low energy ADF shocks such as described earlier herein.The multisite localized pacing can assist in controlling the level oforganization of AF upon which ADFT may depend. Adjustments to the localpacing rates also can be made in real time in response to any sensedchanges to the local AFCL after addition of any ADF shock tier oftherapy, if needed.

AF Therapy Based Upon Single Site Pacing:

As illustrated by the flow chart in FIG. 11, pacing of the atrium alsocan be performed from a single site that is a low potential gradientregion of atrial tissue with the CIPI and S1-S1 intervals being set asproportions of the median AFCL sensed at the single pacing site. Namely,the coupling interval for pacing initiation (CIPI) and the S1-S1interval for the single pacing site are each set to be in an "x-y%"range equal to approximately 70-99%, preferably approximately 80 to 95%,of the determined AFCL. As indicated in FIG. 11, where single sitepacing does not achieve termination the atrial fibrillation episode by afixed number (x_(c)) of pacing attempts, then ADF shocks can be added atthe end of the pacing pulse trains at an S1-S2 interval of 85 to 95%,preferably about 90% of the S1-S1 interval being used. Single sitepacing, instead of multisite pacing, can be used as long as the capturearea created by the single pacing site is large enough to terminate thefibrillation or permit a meaningful reduction of the ADFT.

To illustrate the inventive method of defibrillation, and its advantagesrelative to other defibrillation techniques, the following experimentswere conducted. The experiments are not intended to limit the scope ofthe invention in any respect and should not be so construed.

EXAMPLE 1

Experiments were conducted to study tiered therapy using multisitesynchronous pacing based on multiple sensing sites in conjunction withADF shocks.

Two adult sheep were implanted with a rapid pacer and a right atrialscrew-in pacing lead. A chronic atrial fibrillation model was created inthese sheep by rapid pacing at approximately 400 beats/minute for 10-14weeks. At the conclusion of the rapid pacing period, the rapid pacerswere removed and the atrial fibrillation studies were conducted.

The two sheep each were anesthetized with isoflurane, arterial andvenous access was established and a median sternotomy was performed. AFwas induced using programmed stimulation or by burst pacing. Ag/AgClpacing and sensing electrodes, each about 1 mm in diameter, were placedat three epicardial sites of the high right atrium, the low right atriumand the mid-lower right atrium with the chest walls closed by surgicalclamps after instrumentation were used for these studies. The atrialdefibrillation lead configuration was RA/SVC to CS. The CSdefibrillation electrode was constructed to be 6 French in diameter and5 cm in length. The RA/SVC defibrillation electrode was a standardVentritex lead (Model SVC-02). Atrial fibrillation was induced by rapidatrial pacing.

Both sheep were subjected to each of therapy Trials 1-3 described below.The numerical results for ADFT voltage and ADFT current that are setforth in Table 1 are reported as the average values " the standarddeviation for both tested sheep for a given Trial.

In Trial 1, a plurality of local AFCLs were measured in real time viathe array of sensing electrodes over a duration of 1-2 seconds. MedianAFCL values were calculated for each sensed atrial site, and the medianAFCL values for the three sites were in the range of 90-134 millisecondsfor both sheep. The minimum median AFCL for the three pacing sites ofeach tested sheep was used in the calculation of the uniform S1-S1interval applied to all three pacing sites of the sheep being tested.CIPI was set equal at approximately 90% with respect to the minimumAFCL. Then, the three pacing sites, viz., the high right atrium, lowright atrium and the mid-lower right atrium, were paced synchronouslywith no delay for two seconds with the S1-S1 interval set atapproximately 90% of the minimum AFCL. An ADF shock was delivered at theend of the pacing train with CIDS set equal to 100% of the S1-S1interval used.

In Trial 2, the same protocol as Trial 1 was used except that an ADFshock was delivered at the end of the pacing train with CIDS set equalto 90% of the S1-S1 interval used.

For sake of comparison, and as Trial 3, a regular ADF therapy with nopacing was applied to the sheep. The results of Trials 1-3 aresummarized in Table 1 below. The CIDS interval (S1-S2), ADFT voltagesand energy required for defibrillation are reported for each type oftherapy investigated under this example.

                  TABLE 1                                                         ______________________________________                                                                              ADFT                                                      CIDS        ADFT    Energy                                  Trial Therapy Type                                                                              (S1-S2)     Voltage (joules)                                ______________________________________                                        1     Hybrid*     100% of S1--S1                                                                            220 ± 20                                                                           1.39 ± 0.5                           2     Hybrid*      90% of S1--S1                                                                            120 ± 40                                                                           0.38 ± 0.4                           3     Regular ADF**                                                                             none        210 ± 40                                                                           1.35 ± 0.4                           ______________________________________                                         *: tiered therapy with pacing followed by ADF shock                           **: no pacing                                                            

The results summarized in Table 1 reveal an approximate 73% reduction inthe energy requirements for ADF in Trial 2 representing the presentinvention versus Trial 1, and an approximate 72% reduction in the energyrequirements for ADF in Trial 2 versus Trial 3. These results show theimportance of not only combining pacing with the ADF shocks but also thesensitivity of the results to the proportionality of the S1-S2 intervalsetting to the S1-S1 interval setting.

EXAMPLE 2

Experiments were conducted to study tiered therapy using multisitesynchronous pacing based on single site sensing in conjunction with ADFshocks.

Two adult sheep were implanted with a rapid pacer and a right atrialscrew-in pacing lead. A chronic atrial fibrillation model was created inthese sheep by rapid pacing at approximately 400 beats/minute for 10-14weeks. At the conclusion of the rapid pacing period, the rapid pacerswere removed and the atrial fibrillation studies were conducted.

The two sheep each were anesthetized with isoflurane, arterial andvenous access was established and a median sternotomy was performed. AFwas induced using programmed stimulation or by burst pacing. Ag/AgClpacing/sensing electrodes (1 mm diameter) were placed at threeepicardial sites of the high right atrium, low right atrium andmid-lower right atrium with the chest walls closed by surgical clampsafter instrumentation were used for these studies. The atrialdefibrillation lead configuration was RA/SVC to CS. The CSdefibrillation electrode was constructed to be 6 French in diameter and5 cm in length. The RA/SVC defibrillation electrode was a standardVentritex lead (Model SVC-02). Atrial fibrillation was induced by rapidatrial pacing.

Both sheep were subjected to each of therapy Trials 1-3 described below.The numerical results for ADFT voltage and ADFT current that are setforth in Table 2 are reported as the average values " the standarddeviation for both tested sheep for a given Trial.

In Trial 1, the median AFCL was measured via a sensing electrode at theBachmann's Bundle in real time over a duration of 1-2 seconds. This AFCLvalue was used as the minimum AFCL value used in the calculation of theuniform S1-S1 interval applied to all the pacing sites. CIPI was setequal at approximately 90% with respect to an activation sensed at theBachmann's Bundle. The three sites, viz., the high right atrium, lowright atrium and the mid-lower atrium were paced synchronously with nodelay for two seconds with the S1-S1 interval set at approximately 90%AFCL. An ADF shock was delivered at the end of the pacing train withCIDS set equal to 100% of the S1-S1 interval used.

In Trial 2, the same protocol as Trial was used except that an ADF shockwas delivered at the end of the pacing train with CIDS set equal to 90%of the S1-S1 interval used.

For sake of comparison, and as Trial 3, a regular ADF therapy with nopacing was applied to the sheep. The results of Trials 1-3 aresummarized in Table 2 below. The CIDS interval (S1-S2), ADFT voltagesand energy required for defibrillation are reported for each type oftherapy investigated under this example.

                  TABLE 2                                                         ______________________________________                                                                              ADFT                                                      CIDS        ADFT    Energy                                  Trial Therapy Type                                                                              (S1-S2)     Voltage (joules)                                ______________________________________                                        1     Hybrid*     100% of S1--S1                                                                            185 ± 25                                                                           1.25 ± 0.3                           2     Hybrid*      90% of S1--S1                                                                            130 ± 30                                                                           0.43 ± 0.2                           3     Regular ADF**                                                                             none        210 ± 40                                                                           1.35 ± 0.4                           ______________________________________                                         *: tiered therapy with pacing followed by ADF shock                           **: no pacing                                                            

The results summarized in Table 2 reveal an approximate 66% reduction inthe energy requirements for ADF in Trial 2 representing the presentinvention versus Trial 1, and an approximate 68% reduction in the energyrequirements for ADF in Trial 2 versus Trial 3. These results show theimportance of not only combining pacing with the ADF shocks but also thesensitivity of the results to the proportionality of the S1-S2 intervalsetting to the S1-S1 interval setting.

Additional experimental studies on multisite synchronous pacing wereconducted in which endocardial electrodes were used instead of theepicardial electrodes for pacing. To estimate how such leads mayperform, an ADF was obtained in one of the two sheep with pacing fromthe following three electrodes: an endocardial screw-in right atriumlead (Pacesetter 1148T), a septal location in the right atrium (DaigLiveWire Duo) and one lower atrial epicardial location. The ADFTs usingthese three pacing sites were found to be even lower than those usingthe three epicardial sites as used in Trial 3 reported above. This was abeneficial finding from a device perspective because it demonstratedthat regular atrial pacing/sensing leads (including screw-in andfloating), and CS leads (with ring pacing/sensing electrodes) can beused to practice the tiered therapy embodiment of this invention.

As can be appreciated from the above, the present invention utilizes oneof several possible pacing regimens to bring large areas of the atriuminto phase-lock, to terminate atrial fibrillation (AF), or,alternatively, the pacing at least improves defibrillation efficacy bybringing such large regions of atrial tissue into phase-lock that anadded tier of ADF shock therapy can bring about atrial defibrillationwith significantly lowered energy requirements.

Although presently preferred embodiments of the present invention havebeen described in detail hereinabove, it should be clearly understoodthat many variations and/or modifications of the basic inventiveconcepts herein taught, which may appear to those skilled in thepertinent art, will still fall within the spirit and scope of thepresent invention, as defined in the appended claims.

For example, it should be noted that so far as the pacing rate isconcerned, CIPI and CIDS have all been described herein to be obtainedon the basis of the AFCL making them patient and episode specific. Itmay also be possible in certain circumstances, such as where a patient'sprior history indicates, that a certain predetermined combination ofpacing and ADFT values may be found to work as well, such as arbitrarilysetting the pacing rate at 100 msec, the CIPI to 90 msec and CIDS to 80msec.

What is claimed is:
 1. A method of treating a heart in need of atrialdefibrillation comprising the steps of:(a) determining an atrialfibrillation cycle length (AFCL) of a heart suffering from afibrillating atrium; and (b) positioning a plurality of defibrillationelectrodes in said atrium; (c) sequentially delivering a plurality ofpulses of electrical current to a single atrial site being a lowpotential gradient region of atrial tissue at a constant pulse-to-pulseinterval rate selected to be a percentage value of said AFCL effectiveto defibrillate said atrium; (d) determining whether atrialdefibrillation is achieved; and (e) where atrial defibrillation is notdetermined in step (d), repeating steps (a), (b) and (c) one or moretimes until atrial defibrillation is achieved.
 2. A method of treating aheart in need of atrial defibrillation comprising the steps of:(a)determining an atrial fibrillation cycle length (AFCL) of a heartsuffering from atrial fibrillation; (b) positioning a plurality ofdefibrillation electrodes in said atrium; (c) sequentially delivering aplurality of pulses of electrical current to a single atrial pacing sitebeing a low potential gradient region of atrial tissue at a constantS1-S1 interval rate of approximately 70% to 99% of said AFCL sufficientto induce phase-lock of atrial tissues; (d) determining whether atrialdefibrillation is achieved; (e) where atrial defibrillation is notdetermined in step (d), repeating steps (a), (b) and (c) a fixed pluralnumber of times; and (f) where atrial defibrillation is not determinedupon completing step (e), delivering a defibrillation shock to saidheart having phase-lock of atrial tissues at an S1-S2 interval rate ofapproximately 85% to 95% of said S1-S1 interval rate effective toterminate atrial fibrillation.
 3. The method of claim 2, wherein saiduniform S1-S1 interval is set to be 80% to 95% of said AFCL.
 4. Themethod of claim 2, wherein the first pulse of the pulse train isdelivered at a time of approximately 70% to 99% of said AFCL after themost recently sensed activation.
 5. The method of claim 2, wherein thefirst pulse of the pulse train is delivered at a time of approximately80% to 95% of said AFCL after the most recently sensed activation. 6.The method of claim 2, wherein said S1-S2 interval rate is set to beabout 90% of said S1-S1 interval.
 7. The method of claim 2, wherein saiddefibrillation shock is less than 1.0 joule.
 8. The method of claim 2,wherein said defibrillation shock is less than 0.5 joules.
 9. A cardiactherapy apparatus for treating an atrium in need of atrialdefibrillation, comprising:a sensor positioned proximate an atriallocation of said atrium for generating electrogram signals; a pluralityof defibrillation electrodes capable of delivering an ADF shock to saidatrium; a single pacing electrode positioned adjacent a low potentialgradient region of said atrium capable of delivering pacing pulses tosaid atrial low potential gradient region; signal processing circuitryfor receiving said electrogram signals from said sensor and beingcapable of detecting an atrial fibrillation episode based on saidelectrogram signals, determining an atrial fibrillation cycle length(AFCL) at said atrial location based on said electrogram signals, andgenerating control signals for activating said electrode such that saidelectrode is capable of (i) delivering pacing pulse trains to saidatrium whereby the first pulse delivered of said pulse train isdelivered at a time of approximately 70% to 99% of said AFCL after themost recently sensed activation and said pacing pulse trains can bethereafter delivered at an S1-S1 interval rate for said pacing sitebased as a 70-99% proportion of said AFCL and (ii) delivering an ADFshock at the end of the last pacing pulse train where a determinationhas been made that pacing pulse trains alone fail to terminate atrialfibrillation.
 10. The cardiac therapy apparatus of claim 9, wherein saidsignal processing circuitry includes a microprocessor controller, saidcontroller connected electrically to said sensors and said electrodes.11. The cardiac therapy apparatus of claim 9, wherein said apparatus isan implantable cardioverter-defibrillator device.